Carnitor

CLINICAL PHARMACOLOGY

CARNITOR® (levocarnitine) is a naturally
occurring substance required in mammalian energy metabolism. It has been shown
to facilitate long-chain fatty acid entry into cellular mitochondria, thereby
delivering substrate for oxidation and subsequent energy production. Fatty
acids are utilized as an energy substrate in all tissues except the brain. In
skeletal and cardiac muscle, fatty acids are the main substrate for energy
production.

Primary systemic carnitine deficiency is characterized by
low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not
been possible to determine which symptoms are due to carnitine deficiency and
which are due to an underlying organic acidemia, as symptoms of both
abnormalities may be expected to improve with CARNITOR® . The
literature reports that carnitine can promote the excretion of excess organic
or fatty acids in patients with defects in fatty acid metabolism and/or
specific organic acidopathies that bioaccumulate acylCoA esters.1-6

Secondary carnitine deficiency can be a consequence of
inborn errors of metabolism. CARNITOR® may alleviate the metabolic
abnormalities of patients with inborn errors that result in accumulation of
toxic organic acids. Conditions for which this effect has been demonstrated
are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium
chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication
occurs in these patients due to the accumulation of acylCoA compounds that
disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA
compound to its free acid results in acidosis which can be life-threatening.
Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which
is quickly excreted. Carnitine deficiency is defined biochemically as
abnormally low plasma concentrations of free carnitine, less than 20
μmol/L at one week post term and may be associated with low tissue and/or
urine concentrations. Further, this condition may be associated with a plasma
concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or
abnormally elevated concentrations of acylcarnitine in the urine. In premature
infants and newborns, secondary deficiency is defined as plasma levocarnitine
concentrations below age-related normal concentrations.

Pharmacokinetics

In a relative bioavailability study in 15 healthy adult
male volunteers, CARNITOR® Tablets were found to be bio-equivalent
to CARNITOR® Oral Solution. Following 4 days of dosing with 6
tablets of CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® oral
solution b.i.d., the maximum plasma concentration (Cmax) was about 80
μmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3
hours.

The plasma concentration profiles of levocarnitine after
a slow 3 minute intravenous bolus dose of 20 mg/kg of CARNITOR® were
described by a two-compartment model. Following a single i.v. administration,
approximately 76% of the levocarnitine dose was excreted in the urine during
the 0-24h interval. Using plasma concentrations uncorrected for endogenous
levocarnitine, the mean distribution half life was 0.585 hours and the mean
apparent terminal elimination half life was 17.4 hours.

The absolute bioavailability of levocarnitine from the
two oral formulations of CARNITOR® , calculated after correction for
circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3%
for CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® Oral
Solution.

Total body clearance of levocarnitine (Dose/AUC including
endogenous baseline concentrations) was a mean of 4.00 L/h.

Levocarnitine was not bound to plasma protein or albumin
when tested at any concentration or with any species including the human.9

Metabolism And Excretion

In a pharmacokinetic study where five normal adult male
volunteers received an oral dose of [3H-methyl]-L-carnitine
following 15 days of a high carnitine diet and additional carnitine supplement,
58 to 65% of the administered radioactive dose was recovered in the urine and
feces in 5 to 11 days. Maximum concentration of [3H-methyl]-L-carnitine
in serum occurred from 2.0 to 4.5 hr after drug administration. Major
metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of
the administered dose) and [3H]-γ-butyrobetaine, primarily in
feces (0.44% to 45% of the administered dose). Urinary excretion of
levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine
was less than 1% of the administered dose.10

After attainment of steady state following 4 days of oral
administration of CARNITOR® Tablets (1980 mg q12h) or Oral Solution
(2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of
levocarnitine during a single dosing interval (12h) was about 9% of the orally
administered dose (uncorrected for endogenous urinary excretion).